1 2 3 4 Tetrahydroisoquinolines derivatives as urotensin II receptor antagonists

ABSTRACT

The invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives of formula (I) and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as neurohormonal antagonists especially urotensin II antagonists.

FIELD OF THE INVENTION

[0001] The present invention relates to novel1,2,3,4-tetrahydroisoquinoline derivatives of the general formula 1 andtheir use as active ingredients in the preparation of pharmaceuticalcompositions. The invention also concerns related aspects includingprocesses for the preparation of the compounds, pharmaceuticalcompositions containing one or more compounds of the general formula 1and especially their use as neurohormonal antagonists.

BACKGROUND OF THE INVENTION

[0002] Urotensin II is a cyclic 11-amino acid peptide that has somesequence similarity to, but is not homologous with, somatostatin-14.Urotensin II was first isolated and sequenced from fish spinal cord (BemH A, Pearson D, Larson B A, Nishioka R S. Neurohormones from fish tails:the caudal neurosecretory system. I. “Urophysiology” and the caudalneurosecretory system of fishes. Recent Prog. Horm. Res. (1985) 41,533-552), and has since been found in a wide variety of vertebrate andinvertebrate species. Human urotensin II is synthesized in a prepro-formfrom a single gene located at chromosome 1p36.21, and two cDNA splicevariants which differ in their putative signal peptide sequence havebeen isolated from human colon tumor and human placenta (GenBankAccession Nr. 095399). The putative prohormone convertase dibasiccleavage site is strictly conserved across species. The mature 11-aminoacid peptide contains a C-terminal disulfide-bridged 6-amino acid loopwhich is also strictly conserved, while the N-terminal portion of themature cyclic peptide can vary considerably across species.

[0003] Urotensin II exerts potent and complex hemodynamic actions inmammals (Douglas S A, Sulpizio A C, Piercy V, Sarau H M, Ames R S, AlyarN V, Ohlstein E H, Willette R N. “Differential vasoconstrictor activityof human urotensin-II in vascular tissue isolated from the rat, mouse,dog, pig, marmoset and cynomolgus monkey.” Br. J. Pharmacol. (2000) 131,1262-1274. Douglas, SA, Ashton D J, Sauermelch C F, Coatney R W,Ohlstein D H, Ruffolo M R, Ohlstein E H, Aiyar N V, Willette R “HumanUrotensin-II is a potent vasoactive peptide: pharmacologicalcharacterization in the rat, mouse, dog and primate.” J. Cardiovasc.Pharmacol. (2000) 36, Suppl 1:S163-6). The peptide effectivelyconstricts isolated mammalian arteries. The potency of vasoconstrictionis an order of magnitude greater than that of endothelin-1. Theseeffects appear to be mediated at least in part via the actions ofurotensin II on a G-protein coupled receptor named GPR-14 or SENR (AmesR S, et al. “Human urotensin-II is a potent vasoconstrictor and agonistfor the orphan receptor GPR14.” Nature. (1999) 401, 282-6. Mori M, SugoT, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y,Kurokawa T, Onda H, Nishimura 0, Fujino M. “Urotensin II is theendogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14)”Biochem. Biophys. Res. Commun. (1999) 265, 123-9. Liu Q, Pong S S, ZengZ, et al. “Identification of urotensin II as the endogenous ligand forthe orphan G-protein-coupled receptor GPR14” Biochem. Biophys. Res.Commun. (1999) 266, 174-178.) GPR14 is expressed in arterial (but notvenous) smooth muscle cells, on atrial and ventricular cardiac myocytes,in pancreas, kidney, and in the brain.

[0004] In addition to its vasoconstrictive actions, urotensin IIpotently affects atrial and ventricular muscle contraction (Russell F D,Molenaar P, and O'Brien D M “Cardiostimulant effects of urotensin-II inhuman heart in vitro”. Br J Pharmacol (2001) 132, 5-9).

[0005] Urotensin II stimulates cellular proliferation, migration andcollagen synthesis in cardiac fibroblasts (Tzandis A, et al., “UrotensinII stimulates collagen synthesis by cardiac fibroblasts and hypertrophicsignaling cardiomyocytes via G(alpha)q and Ras-dependent pathways”. J.Am. Coll. Cardiol. (2001) 37, 164A.) and in neonatal myocytes (Zou Y,Nagai R, and Yamazaki T, “Urotensin II induces hypertrophic responses incultured cardiomyocytes from neonatal rats”. FEBS Lett (2001) 508,57-60). Urotensin II is produced by cancer cell lines and its receptoris also expressed in these cells. (Takahashi K, et al., “Expression ofurotensin II and urotensin II receptor mRNAs in various human tumor celllines and secretion of urotensin II-like immunoreactivity by SW-13adrenocortical carcinoma cells”. Peptides (2001) 22, 1175-9).

[0006] Urotensin II modulates' glucose-stimulated pancreatic release ofinsulin (Silvestre R A, et al., “Inhibition of insulin release byurotensin II—a study on the perfused rat pancreas”. Horm Metab Res(2001) 33, 379-81). Elevated circulating levels of urotensin II aredetected in humans susceptible to high-altitude pulmonary edema, and inpatients awaiting kidney transplantation (Totsune K, et al., “Role ofurotensin II in patients on dialysis”. Lancet (2001) 358, 810-1).

[0007] Urotensin II and its receptor are found in spinal cord and braintissue, and intracerebroventricular infusion of urotensin II into miceinduces behavioral changes (Gartlon J, et al., “Central effects ofurotensin-II following ICV administration in rats”. Psychopharmacology(Berlin) (2001) 155, 426-33).

[0008] Substances with the ability to block the actions of urotensin IIare accordingly expected to prove useful in the treatment of variousdiseases. WO-2001/45694 discloses certain sulfonamides as urotensin IIreceptor antagonists, and their use to treat diseases associated with aurotensin II imbalance. WO-2001/45700 discloses certain pyrrolidines asurotensin II receptor antagonists and their use to treat diseasesassociated with a urotensin II imbalance. WO-2001/45711 disclosescertain pyrrolyl and pyridyl derivatives as urotensin II receptorantagonists and their use to treat diseases associated with a urotensinII imbalance. WO-2002/00606 discloses certain biphenyl compounds usefulas urotensin II receptor antagonists, and WO-2002/02530 also disclosescertain compounds useful as urotensin II receptor antagonists.

[0009] The present invention comprises 1,2,3,4-tetrahydroisoquinolinederivatives which are novel compositions of matter and which areurotensin II receptor antagonists. EP 428434 discloses certainalkylureidopyridines as neurokinin and substance P antagonists.WO-99/21835 discloses certain ureidoquinolines as H+-ATPase and boneresorption inhibitors. WO-01/009088 discloses certain substitutedheteroarylureas as inhibitors of the CCR-3 receptor.

DESCRIPTION OF THE INVENTION

[0010] The present invention relates to compounds of the general formula1,

[0011] wherein

[0012] X represents —CH₂—, —CH₂CH₂—, —C(CH₃)₂—;

[0013] Y represents oxygen, NH;

[0014] n represents the numbers 1 or 2;

[0015] Z represents quinolin-4-yl which may be mono-substituted withlower alkyl in the positions 2, 6, or 8, or di-substituted with loweralkyl in the positions 2, 6 or 2,8; [1,8]naphthyridin-4-yl which may besubstituted in position 7 with lower alkyl; pyridin-4-yl which may besubstituted in position 2 with R⁷R⁸N— and additionally in position 6with hydrogen or lower alkyl;

[0016] R¹ represents naphthalen-1-yl; naphthalen-2-yl;benzo[1,3]dioxol-5-yl; benzyl, or mono-, di-, or tri-substituted benzylsubstituted in the pheny1 ring independently with lower alkyl, loweralkyloxy, trifluoromethyl, halogen, cyano; phenyl, or mono-, di- ortri-substituted phenyl, substituted independently with lower alkyl,lower alkyloxy, trifluoromethyl, halogen, cyano;

[0017] R² represents hydrogen, lower alkyl, aryl or forms with R¹ astyryl group of E or Z geometry, whereby the phenyl ring in the styrylgroup may be mono-, di- or tri-substituted phenyl, substitutedindependently with lower alkyl, lower alkyloxy, trifluoromethyl,halogen, cyano;

[0018] R³, R⁴, R⁵ and R⁶ independently represent hydrogen, cyano,hydroxy, lower alkyloxy, aralkyloxy, lower alkenyloxy, and R⁵additionally represents R⁷R⁸NCO;

[0019] R⁴ and R⁵ together may form with the phenyl ring a five- or asix-membered ring containing one or two oxygen atoms;

[0020] R⁷ and R⁸ independently represent hydrogen, lower alkyl, aryl,aralkyl, or together with the N form a pyrrolidine, piperidine, ormorpholine ring;

[0021] and optically pure enantiomers or diastereomers, mixtures ofenantiomers or diastereomers, diastereomeric racemates, and mixtures ofdiastereomeric racemates; as well as their pharmaceutically acceptablesalts, solvent complexes, and morphological forms.

[0022] In the definitions of the general formula 1 the expression ‘loweralkyl’ means straight or branched chain groups with one to seven carbonatoms, preferably 1 to 4 carbon atoms; or cyclic alkyl groups with threeto six carbon atoms. Preferred examples of lower alkyl groups aremethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl, n-heptyl, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

[0023] The expression ‘lower alkyloxy’ means a group of the formulalower alkyl-O— in which the term ‘lower alkyl’ has the meaningpreviously given. Preferred examples of lower alkyloxy groups aremethoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy,tert-butoxy, cyclopentyloxy, and cyclohexyloxy.

[0024] The expression ‘lower alkenyloxy’ means a group of the formulalower alkenyl-O— in which the term ‘lower alkenyl’ means astraight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms.Preferred examples of lower alkenyloxy groups are allyloxy orpropenyloxy.

[0025] The expression ‘aryl’ means a phenyl or naphthyl group whichoptionally carries one or more substituents, preferably one or twosubstituents, each independently selected from cyano, halogen, loweralkyl, lower alkenyl, lower alkyloxy, lower alkenyloxy, trifluoromethyl,trifluoromethoxy, amino, carboxy and the like. Preferred examples ofaryl groups are phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyanophenyl,4-chlorophenyl, 4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl,2-fluorophenyl, 2-methoxyphenyl, naphthalen-1-yl and naphthalen-2-yl.

[0026] The expression ‘arallyl’ means a lower alkyl group as previouslydefined in which one hydrogen atom has been replaced by an aryl group aspreviously defined. Preferred examples of aralkyl groups are benzyl andbenzyl substituted in the phenyl ring with hydroxy, lower alkyl, loweralkyloxy or halogen.

[0027] The expression ‘aralkyloxy’ means a group of the formulaaralkyl-O— in which the term ‘aralkyl’ has the meaning previously given.Preferred examples of aralkyloxy are benzyloxy and phenethyloxy.

[0028] The present invention encompasses pharmaceutically acceptablesalts of compounds of the general formula 1. This encompasses eithersalts with inorganic acids or organic acids like hydrohalogenic acids,e.g. hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, citric acid, formic acid, acetic acid, maleic acid,tartaric acid, methylsulfonic acid, p-tolylsulfonic acid and the like orin case the compound of formula 1 is acidic in nature with an inorganicbase like an alkali or earth alkali base, e.g. sodium, potassium, orcalcium salts, etc.

[0029] The present invention encompasses different solvation complexesof compounds of general formula 1. The solvation can be effected in thecourse of the manufacturing process or can take place separately, e.g.as a consequence of hygroscopic properties of an initially anhydrouscompound of general formula 1.

[0030] The present invention further encompasses different morphologicalforms, e.g. crystalline forms, of compounds of general formula 1 andtheir salts and solvation complexes. Particular heteromorphs may exhibitdifferent dissolution properties, stability profiles, and the like, andare all included in the scope of the present invention.

[0031] The compounds of the general formula 1 might have one or moreasymmetric carbon atoms and may be prepared in form of optically pureenantiomers or diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates, and mixtures of diastereomeric racemates. Thepresent invention encompasses all these forms. They are prepared bystereoselective synthesis, or by separation of mixtures in a mannerknown per se, i.e. by column chromatography, thin layer chromatography,HPLC, crystallization, etc.

[0032] Preferred compounds of general formula 1 are the compounds ofgeneral formula 2,

[0033] wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Z, and n have the meaninggiven in general formula 1 above.

[0034] Another group of preferred compounds of general formula 1 are thecompounds of general formula 3,

[0035] wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z have the meaninggiven in general formula 1 above.

[0036] Another group of preferred compounds of general formula 1 are thecompounds of general formula 4,

[0037] wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaninggiven in general formula 1 above.

[0038] Another group of preferred compounds of general formula 1 are thecompounds of general formula 5,

[0039] wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaninggiven in general formula 1 above.

[0040] Another group of preferred compounds of general formula 1 are thecompounds of general formula 6,

[0041] wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaninggiven in general formula 1 above.

[0042] Another group of preferred compounds of general formula 1 are thecompounds of general formula 7,

[0043] wherein R¹, R³, R⁴, R⁵, R⁶, X, Y, Z, and n have the meaning givenin general formula 1 above.

[0044] Another group of preferred compounds of general formula 1 are thecompounds of general formula 8,

[0045] wherein Ph is phenyl; mono-, di- or tri-substituted phenyl,substituted independently with hydrogen, lower alkyl, lower alkyloxy,trifluoromethyl, halogen, or cyano; and R³, R⁴, R⁵, R⁶, X, Y, Z, and nhave the meaning given in general formula 1 above.

[0046] Another group of preferred compounds of general formula 1 are thecompounds of general formula 9,

[0047] wherein R¹, R², X, Y, Z, and n have the meaning given in generalformula 1 above.

[0048] Another group of preferred compounds of general formula 1 are thecompounds of general formula 10,

[0049] wherein R¹, R², X, Y, Z, and n have the meaning given in generalformula 1 above.

[0050] Another group of preferred compounds of general formula 1 are thecompounds of general formula 11,

[0051] wherein R¹, R², X, Y, Z, and n have the meaning given in generalformula 1 above.

[0052] Another group of preferred compounds of general formula 1 are thecompounds of general formula 12,

[0053] wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and n have the meaninggiven in general formula 1.

[0054] Another group of preferred compounds of general formula 1 are thecompounds of general formula 13,

[0055] wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and n have the meaninggiven in general formula 1.

[0056] Another group of preferred compounds of general formula 1 are thecompounds of general formula 14,

[0057] wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, Y, and n have themeaning given in general formula 1.

[0058] Another group of preferred compounds of general formula 1 are thecompounds of general formula 15,

[0059] wherein the 1 position of the 1,2,3,4-tetrahydroisoquinoline ringsystem has the R absolute stereochemical configuration, and R¹, R², R³,R⁴, R⁵, R⁶, X, Z, and n have the meaning given in general formula 1.

[0060] Another group of preferred compounds of general formula 1 are thecompounds of general formula 16,

[0061] wherein R³, R⁴, R⁵, and R⁶ are independently hydrogen or loweralkyloxy; and R¹, R², and Z have the meaning given in general formula 1above.

[0062] Examples of particularly preferred compounds of general formula 1are:

[0063]1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0064]1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0065]1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0066]1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0067]1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0068]1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0069]1-(2-{1-[2-(4-Fluoro-phenyl)ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0070]1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl-3-(2-methyl-quinolin-4-yl)-urea

[0071]1-(2-{1-[2-2,4-Difluoro-phenylpethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea

[0072]1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0073]1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea

[0074]1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea

[0075]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0076]1-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0077]1-(2-{1-[(E)-2-(2,4-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0078]1-(2-{1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0079] 1-(2-{1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0080]1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-2-methyl-quinolin-4-yl)-urea

[0081]1-(2-{1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0082]1-(2-{1-[2-(2,5-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0083]1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-2-methyl-quinolin-4-yl)-urea

[0084]1-(2-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0085]1-(2-{1-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0086]1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0087]1-(2-{6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0088]1-(2-{6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0089]1-(2-{6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

[0090]1-(2-{6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolinyl)-urea

[0091]1-[2-6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea

[0092]1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0093]1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-ylyethyl]-3-quinolinyl-urea

[0094]1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea

[0095]1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea

[0096]1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea

[0097]1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0098]1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0099]1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0100]1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0101]1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea

[0102]1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0103]1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0104]1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0105]1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolinyl-urea

[0106]1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0107]1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0108]1-[2-(6,7-Dimethoxy-1-phenoxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0109]1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea

[0110]1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea

[0111]1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0112]1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0113]1-{2-[1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0114]1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0115]1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0116]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0117]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0118]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0119]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea

[0120]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0121]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl}-3-pyridin-4-yl-urea

[0122]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0123]1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0124]1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0125]1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0126]1-{2-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-methyl-quinolin-4-yl)-urea

[0127]1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0128]1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0129]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0130]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0131]1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0132]1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolinyl-urea

[0133]1-{2-[6,7-Dimethoxy-1-3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0134]1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0135]1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0136]1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-yl-urea

[0137]1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0138]1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0139]1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0140]1-{3-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea

[0141]1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea

[0142]1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea

[0143]1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea

[0144]1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolinyl-urea

[0145]1-{3-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea

[0146]1-{2-[5-3,4-Dimethoxy-benzyl>7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-pyridin-4-yl-urea

[0147]1-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-quinolin-4-yl-urea

[0148]1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-pyridin-4-yl-urea

[0149]1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-quinolin-4-yl-urea

[0150]1-[2-(1-Benzhydryl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0151]1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0152]1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0153]1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea

[0154]1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea

[0155]1-{2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0156]1-{2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-yl-urea

[0157]1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea

[0158]1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-yl-urea

[0159]1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0160]1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-2-methyl-quinolin-4-yl)-urea

[0161]1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea

[0162]1-{2-[(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-2-methyl-quinolin-4-yl)-urea

[0163]1-{2-[7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0164]1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea

[0165]1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid methylamide

[0166]1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid propylamide

[0167]1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylicacid dimethylamide

[0168]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea

[0169]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea

[0170]1-[2-(Benzyl-methyl-amino)-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea

[0171]1-[2-(Benzyl-methyl-amino)-6-methyl-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea

[0172]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-[2-(methyl-phenyl-amino)-pyridin-4-yl]-urea

[0173]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-pyrrolidin-1-yl-pyridin-4-yl)-urea

[0174]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methylamino-1-yl-pyridin-4-yl)-urea

[0175] Quinolin-4-yl-carbamic acid2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylester

[0176] Quinolin-4-yl-carbamic acid2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester

[0177] Quinolin-4-yl-carbamic acid2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethylester

[0178] Quinolin-4-yl-carbamic acid3-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester

[0179] Quinolin-4-yl-carbamic acid3-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propylester

[0180] Quinolin-4-yl-carbamic acid3-[1-(3,4-difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester

[0181] Quinolin-4-yl-carbamic acid3-[1-(3,4-dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester

[0182] Quinolin-4-yl-carbamic acid3-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propylester

[0183] Because of their ability to inhibit the actions of urotensin II,the described compounds can be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation or otherdisease states associated with the actions of urotensin II. Examples ofsuch diseases are hypertension, atherosclerosis, angina or myocardialischemia, congestive heart failure, cardiac insufficiency, cardiacarrhythmias, renal ischemia, chronic kidney disease, renal failure,stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine,subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma,chronic obstructive pulmonary disease, high-altitude pulmonary edema,Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonaryedema, pulmonary hypertension, or pulmonary fibrosis. They can also beused for prevention of restenosis after balloon or stent angioplasty,cancer, prostatic hypertrophy, erectile dysfunction, hearing loss,amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock,sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapyand prophylaxis of diabetic complications, complications of vascular orcardiac surgery or after organ transplantation, complications ofcyclosporin treatment, pain, addictions, schizophrenia, Alzheimer'sdisease, anxiety, obsessive-compulsive behavior, epileptic seizures,stress, depression, dementias, neuromuscular disorders,neurodegenerative diseases, as well as other diseases related to adysregulation of urotensin II or urotensin II receptors.

[0184] These compositions may be administered in enteral or oral forme.g. as tablets, dragees, gelatine capsules, emulsions, solutions orsuspensions, in nasal form like sprays or rectally in form ofsuppositories. These compounds may also be administered inintramuscular, parenteral or intravenous form, e.g. in form ofinjectable solutions.

[0185] These pharmaceutical compositions may contain the compounds offormula 1 as well as their pharmaceutically acceptable salts incombination with inorganic and/or organic excipients, which are usual inthe pharmaceutical industry, like lactose, maize or derivatives thereof,talcum, stearic acid or salts of these materials.

[0186] For gelatine capsules vegetable oils, waxes, fats, liquid orhalf-liquid polyols etc. may be used. For the preparation of solutionsand sirups e.g. water, polyols, saccharose, glucose etc. are used.Injectables are prepared by using e.g. water, polyols, alcohols,glycerin, vegetable oils, lecithin, liposomes etc. Suppositories areprepared by using natural or hydrogenated oils, waxes, fatty acids(fats), liquid or half-liquid polyols etc.

[0187] The compositions may contain in addition preservatives,stabilisation improving substances, viscosity improving or regulatingsubstances, solubility improving substances, sweeteners, dyes, tasteimproving compounds, salts to change the osmotic pressure, buffer,anti-oxidants etc.

[0188] The compounds of general formula 1 may also be used incombination with one or more other therapeutically useful substancese.g. α- and β-blockers like phentolamine, phenoxybenzamine, atenolol,propranolol, Uimolol, metoprolol, carteolol, carvedilol, etc.; withvasodilators like hydralazine, minoxidil, diazoxide, flosequinan, etc.;with calcium-antagonists like diltiazem, nicardipine, nimodipine,verapamil, nifedipine, etc.; with angiotensin convertingenzyme-inhibitors like cilazapril, captopril, enalapril, lisinopriletc.; with potassium channel activators like pinacidil, chromakalim,etc.; with angiotensin receptor antagonists like losartan, valsartan,candesartan, irbesartan, eprosartan, telmisartan, and tasosartan, etc.;with diuretics like hydrochlorothiazide, chlorothiazide, acetolamide,bumetamide, furosemide, metolazone, chlortalidone, etc.; withsympatholytics like methyldopa, clonidine, guanabenz, reserpine, etc.;with endothelin receptor antagonists like bosentan, tezosentan,darusentan, atrasentan, enrasentan, or sitaxsentan, etc.; withanti-hyperlipidemic agents like lovastatin, pravistatin, fluvastatin,atorvastatin, cerivastatin, simvastatin, etc.; and other therapeuticswhich serve to treat high blood pressure, vascular disease or otherdisorders listed above.

[0189] The dosage may vary within wide limits but should be adapted tothe specific situation. In general the dosage given daily in oral formshould be between about 3 mg and about 3 g, preferably between about 10mg and about 1 g, especially preferred between 5 mg and 300 mg, peradult with a body weight of about 70 kg. The dosage should beadministered preferably in 1 to 3 doses of equal weight per day. Asusual children should receive lower doses which are adapted to bodyweight and age.

[0190] Compounds of the general formula 1 can be prepared using methodsgenerally known in the art, according to the general sequence ofreactions outlined below. For simplicity and clarity reasons sometimesonly a few of the possible synthetic routes that lead to compounds ofgeneral formula 1 are described.

[0191] For the synthesis of compounds of general formula 1 generalsynthetic routes illustrated in Schemes A through E can be employed. Insome instances one or another of the various groups (R¹ to R⁹, X, Y, Z,n) might be incompatible with the assembly illustrated in Schemes Athrough E and so will require the use of protecting groups. The use ofprotecting groups is well known in the art (see for example “ProtectiveGroups in Organic Synthesis, T. W. Greene, Wiley-Interscience, 1981).Particular groups that may require protection are amines (protected asamides or carbamates), alcohols (protected as esters or ethers) andcarboxylic acids (protected as esters). For the purposes of thisdiscussion, it will be assumed that such protecting groups as arenecessary are in place.

[0192] 1,2,3,4-Tetrahydroisoquinolines and1,2,3,4-tetrahydrobenz[c]azepines of general structure I in Schemes Athrough C are either commercially available or are prepared in racemicor optically active form by methods well known in the art. For instancethey can be prepared by a ring-closing condensation reaction of amidesderived from the corresponding phenylethylamines or phenylpropylaminesand the appropriate carboxylic acid under the action of POCl₃ or PCl₅,followed by treatment with a reducing agent such as NaBH₄ (Whaley W M,Govindachari T R “The preparation of 3,4-dihydroisoquinolines andrelated compounds by the Bischler-Napieralski reaction.” Org. React.(1951) 6, 74-106. Finkelstein J, Chiang E, Brossi A “Synthesis of1,2,3,4-tetrahydro-1,1,2,3,3,4,4,-heptamethyl-6,7-dimethoxyisoquinolineand related compounds as potential hypotensive agents.” J. Med. Chem.(1971) 14, 584-588. Ukaji Z, Shimizu Y, Kenmoku Y, Ahmend A, Inomata K“Catalytic asymmetric addition of dialkylzinc to 3,4-dihydroisoquinolineN-oxides utilizing tartaric acid ester as a chiral auxiliary.” Bull.Chem. Soc. Jpn. (2000), 73, 447-452. Zheng W, Nikulin V I, Konkar A A,Vansal S S, Shams G, Feller D R, Miller D D“2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: novelselective beta3-adrenoceptor antagonists.” J Med Chem (1999), 42,2287-2294). Substantially enantiomerically pure1-substituted-2-tetrahydroisoquinoline andI-substituted-2-tetrahydrobenzazepine derivatives are prepared byanalogous methods (Polniaszek R. P. et al., J. Am. Chem. Soc. (1989)111, 4859-4863). The key step of this asymmetric synthesis is astereoselective hydride reduction of a chiral iminium ion obtained byBischler-Napieralski reaction. For the preparation of(R)-1-substituted-2-tetrahydroisoquinoline derivatives the chiralityresident in the substrate is derived from commercially available(R)-(+)-α-phenethylamine.

[0193] According to schemes A or B, appropriate1,2,3,4-tetrahydroisoquinolines or 1,2,3,4-tetrahydrobenz[c]azepines ofgeneral structure I are N-alkylated with suitably protected aminoalkylhalides It or hydroxyalkyl halides III. Removal of the protecting groupprovides the amines IV or alcohols V. The intermediates IV and V arefurther elaborated to the final compounds of general formula 1 bystepwise treatment with a carbonylating agent such ascarbonyldiimidazole, followed by reaction with a suitable amine VI inthe presence of a strong base such as sodium hexamethyldisilazide. Thisprovides the final compounds VII and VIII, which correspond to generalformula 1, in which Y is NH or O, respectively, and in which n, X, Z andR¹ to R⁶ have the definitions given in general formula 1.

[0194] An alternative synthetic route to compounds of general formula 1is illustrated in Scheme C. Thus, carboxylic acids of general structureIX are converted to their corresponding acyl azide, for example by thetreatment with DPPA in a polar aprotic solvent such as DMF. The crudeacyl azide is subjected to thermal rearrangement in an inert solventsuch as toluene, to provide the corresponding isocyanate. Reaction ofthe crude isocyanate with alkyl amines of general structure IV or withalkyl alcohols of general structure V provides the target compounds VIIor VII in which n, X, Y, Z and R¹ to R⁶ have the definitions given ingeneral formula 1.

[0195] An alternative synthetic route to compounds of general formula 1is illustrated in Scheme D. Thus, 1,2,3,4-tetrahydroisoquinolines ofgeneral structure I are N-alkylated with compounds of general structureX (Russell RK et al. “Thiophene Systems. 9 ThienopyrimidinedioneDerivatives as Potential Antihypertensive Agents” J Med Chem 1988, 31,1786-1793) in an aprotic solvent such as THF in the presence of ascavenger base such as NaHCO₃ or di-isopropylethylamine, to provide thetarget compounds XI in which n, X, Y, Z and R¹ to R⁶ have thedefinitions given in general formula 1.

[0196] The preparation of the requisite intermediates of generalstructure X is illustrated in Scheme E, wherein Y, Z and n have themeaning given in general formula 1, and Hal stands for a halogen atomsuch as chloride. Commercially available or well-known heteroaryl aminesof general structure VI are reacted with commercially available orwell-known haloalkyl isocyanates, or haloalkyl chloroformates.Alternatively, compounds of general structure X are prepared by reactionof the isocyanate derived from heteroaryl carboxylic acids IX.

[0197] The foregoing general description of the Invention will now befurther Illustrated by a number of examples which do not at all limitthe scope of the invention.

EXAMPLES

[0198] List of Abbreviations:

[0199] AcOH acetic acid

[0200] BSA bovine serum albumin

[0201] CDI carbonyldiimidazole

[0202] DIPEA diisopropylethylamine

[0203] DMAP 4-dimethylaminopyridine

[0204] DMF dimethylformamide

[0205] DMSO dimethylsulfoxide

[0206] DPPA diphenylphosphorylazide

[0207] EDC N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide

[0208] EDTA ethylenediamine tetra-acetic acid

[0209] EtOAc ethyl acetate

[0210] Et₂O diethyl ether

[0211] Hex hexane

[0212] HOBt 1-hydroxybenzotriazole

[0213] HPLC high performance liquid chromatography

[0214] HV high vacuum conditions

[0215] LC-MS liquid chromatography-mass spectroscopy

[0216] LAH lithium aluminum hydride

[0217] MeOH methanol

[0218] min minutes

[0219] MHz megahertz

[0220] NaHMDS sodium bis(trimethylsilyl)amide

[0221] NMR nuclear magnetic resonance

[0222] ppm part per million

[0223] PBS phosphate-buffered saline

[0224] PyBOP (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate

[0225] rt room temperature

[0226] sat. saturated

[0227] TEA triethylamine

[0228] TFA trifluoroacetic acid

[0229] THF tetrahydrofuran

[0230] TLC thin layer chromatography

[0231] t_(R) retention time

[0232] Reactions are routinely performed under an inert atmosphere suchas N₂ gas in air dried glassware. Solvents are used as received from thevendor. Evaporations are performed in a rotary evaporator at reducedpressure and a water bath temperature of 50° C. LCMS characterizationsare performed on a Finnigan HPI 100 platform using ESI ionization mode,and positive ion detection with a Navigator AQA detector. Analyticalliquid chromatographic separations are performed on a C18 column of4.6×30 mm dimensions and a mobile phase consisting of a 6 minutegradient of 2-95% CH₃CN in water containing 0.50% formic acid at a flowrate of 0.45 mL/min. Retention time (t_(R)) is given in min. TLC isperformed on pre-coated silica gel 60 F₂₅₄ glass-backed plates (Merck).Preparative HPLC is performed on a Varian/Gilson platform using a C18column of 21×60 mm dimensions and a mobile phase consisting of agradient of 2-95% CH₃CN in water containing 0.5% formic acid.

[0233] Preparation of Intermediates.

Example A

[0234] A1.(4-Fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline.

[0235] 2-(3,5-Dimethoxy-phenyl)-ethylamine.

[0236] To a suspension of LiAlH₄ (1.76 g, 46.4 mmol) in THF (30 mL) isadded at 0° C. dropwise a solution of1,3-dimethoxy-5-(2-nitro-vinyl)-benzene (2.43 g, 11.6 mmol; Gairaud C B,Lappin G R, J Org Chem 1953, 18, 1) in THF (70 mL). The mixture isstirred for 30 min at this temperature and then at reflux for 4 h. Thereaction mixture is quenched by the subsequent addition of 2 N NaOH (20mL) and stirred for another 15 min at ambient temperature. The aqueoussolution is extracted three times with EtOAc. The combined organiclayers are dried with anhydrous MgSO₄, filtered and concentrated to givethe title compound as a yellow oil.

[0237] N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-2-(4-fluoro-phenyl)-acetamide.

[0238] To a solution of 2-(3,5-dimethoxy-phenyl)-ethylamine (1.01 g,5.57 mmol) in anhydrous DMF (50 mL) is added 4-fluorophenyl acetic acid(860 mg, 5.57 mmol), PyBOP (3.17 g) and N-ethyldiisopropylamine (2.2 mL,12.8 mmol). The mixture is stirred at rt for 14 h. Water (60 mL) isadded, and the mixture is extracted with EtOAc (4×60 mL). The combinedorganic phases are washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by silica gel columnchromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellowoil.

[0239]1-(4-Fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoguinoline.

[0240] To a stirred solution ofN-[2-(3,5-dimethoxy-phenyl)-ethyl]-2-4-fluoro-phenyl)-acetamide (404 mg,1.27 mmol) in CH₃CN (3 mL) is added POCl₃ (350 μL, 3.82 mmol). Thereaction mixture is stirred at reflux for 30 min. Concentration underreduced pressure gives a residual oil, which is dissolved in MeOH (10mL). To this solution is added portionwise NaBH₄ (340 mg, 8.61 mmol) at0° C. The reaction mixture is allowed to warm to rt and is stirred for14 h. The reaction mixture is poured into water (15 mL) and extractedfour times with CH₂Cl₂. The combined organic layers are dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue is purified by flash column chromatography (CH₂Cl₂/MeOH, 9:1) togive the title compound as a brown oil.

Examples A2-A4

[0241] The following starting materials are prepared by the method ofexample A1:

[0242] A2.1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0243] A3.1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0244] A4.1-(3-Fluoro-4-methoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0245] A5.1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4,-tetrahydro-isoguinoline.

[0246]N-[2-(3,5-Dimethoxy-phenyl)-ethyl]-3-(4-fluoro-phenyl)-propionamide.

[0247] 2-(3,5-Dimethoxy-phenyl)ethylamine (1.20 g, 6.62 mmol) isdissolved in anhydrous DMF (50 mL), and 3-(4-fluorophenyl) propionicacid (1.113 g, 6.62 mmol), PyBOP (3.77 g) and DIPEA (2.61 mL, 15 mmol)are added. The mixture is stirred at rt for 14 h. Water (60 mL) isadded, and the mixture is extracted with EtOAc (4×60 mL). The combinedorganic phases are washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by silica gel columnchromatography (EtOAc/Hex, 7:3) to afford the title compound as a yellowoil.

[0248]1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4,-tetrahydro-isoguinoline.

[0249] To a stirred solution ofN-[2-(3,5-dimethoxy-phenyl)-ethyl]-3-(4-fluoro-phenyl)-propionamide(1.25 g, 3.77 mmol) in CH₃CN (12 mL) is added POCl₃ (1.04 mL, 11 mmol).The reaction mixture is stirred at reflux for 30 min. Concentrationunder reduced pressure gives a residual oil, which is dissolved in MeOH(35 mL). To this solution is added portionwise NaBH₄ (1.00 g, 26.4 mmol)at 0° C. and the reaction mixture is allowed to warm to rt and stir for14 h. The mixture is poured into water (40 mL) and extracted with CH₂Cl₂(4×40 mL). The combined organic layers are dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue ispurified by flash column chromatography (CH₂Cl₂/MeOH, 9:1) to give thetitle compound as a brown oil.

Examples A6-A7

[0250] The following starting materials are prepared according to themethod of example A5:

[0251] A6.1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0252] A7.1-[2-(3,4-Difluoro-phenylyethyl]-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0253] A8.6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline.

[0254]N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-(3-methoxy-phenyl)-propionamide.

[0255] To a suspension of 3-(3-methoxy-phenyl)-propionic acid (1.19 g,6.62 mmol) and 3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride(1.33 g, 6.95 mmol) in THF (20 mL) is added2-(3,4-dimethoxy-phenyl)-ethylamine (1.20 g, 6.62 mmol). The mixture isstirred at rt for 14 h. The mixture is poured onto H₂O (100 mL) andEtOAc (100 mL). The organic layer is washed successively with saturatedsodium hydrogen carbonate solution, 10% citric acid and saturated sodiumchloride solution. The resulting organic layer is concentrated underreduced pressure to give the title compound.

[0256]6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline.

[0257] To a solution ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-3-methoxy-phenyl) propion-amide(2.21 g, 6.44 mmol) in THF (50 mL) is added POCl₃ (4.91 g, 32.2 mmol)and the resulting solution is refluxed for 1 h. After cooling to rt thesolvent is removed under reduced pressure. The resulting oil is treatedwith methanol (20 mL) and evaporated again. The residue is dissolved inabsolute methanol (40 mL) cooled to 0° C. and NaBH4 (1.21 g, 32.0 mmol)is added in portions. The resulting mixture is stirred at rt for 16 h,and then evaporated. To this residue is added water (150 mL). Theaqueous layer is extracted with CH₂Cl₂ (3×50 mL). The combined extractsare dried over MgSO₄ and concentrated to give the title compound.

Examples A9-A45

[0258] The following starting materials are prepared according to themethod of example A8:

[0259] A9.1-[(E)-2-(2,3-Difluoro-phenyl)vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0260] A10.1-[(E)-2-(2,4-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0261] A11.1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0262] A12.1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0263] A13.1-[2-(2,5-Difluoro-phenylyethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0264] A14.1-[2-3,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0265] A15.1-[2-3,4-Dimethoxy-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0266] A16.1-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0267] A17.1-[2-(4-Fluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0268] A18.6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

[0269] A19.6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

[0270] A20.6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,2,3,4-tetrahydro-isoquinoline

[0271] A21. 6,7-Dimethoxy-1-phenethyl-1,2,3,4-tetrahydro-isoquinoline

[0272] A22.1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0273] A23.1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0274] A24.1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0275] A25.1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0276] A26.1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0277] A27.1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline

[0278] A28.1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0279] A29.1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0280] A30.1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0281] A31.1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0282] A32. 1-Benzhydryl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0283] A33.1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0284] A34. 1-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0285] A35.6-(3,4-Dimethoxy-benzyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]-isoquinoline

[0286] A36.6,7-Dimethoxy-1-(1-phenyl-propyl)-1,2,3,4-tetrahydro-isoquinoline

[0287] A37.6,7-Dimethoxy-1,2,3,4-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

[0288] A38.6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

[0289] A39.6,7-Dimethoxy-1-(3-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

[0290] A40.6,7-Dimethoxy-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline

[0291] A41.6,7-Dimethoxy-1-naphthalen-2-ylmethyl-1,2,3,4-tetrahydro-isoquinoline

[0292] A42.6,7-Dimethoxy-1-phenoxymethyl-1,2,3,4-tetrahydro-isoquinoline

[0293] A43.7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline

[0294] A44.1-(3,4-Dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline

[0295] A45.1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0296] 3-(3,4-Dimethoxy-phenyl)-propionamide.

[0297] To a stirred solution of 3-(3,4-dimethoxy-phenyl)-propionic acid(10.0 g, 47.6 mmol) in dry THF (175 mL), under nitrogen, is added TEA(7.3 ml, 52.4 mmol). The resulting mixture is cooled to −10° C. beforeethyl chloroformate (5.0 ml, 52 mmol) is added dropwise. After stirringat −10° C. (20 min), ammonium hydroxide (25% in water, 105 ml) in THF(105 mL) is added and the mixture is stirred at −15° C. for 30 min andthen at rt for 1.5 h. The reaction mixture is concentrated in vacuo,extracted three times with CH₂Cl₂ and the combined organic extracts arewashed with saturated aqueous NaHCO₃ and brine. The organic phase isdried over anhydrous MgSO₄, filtered and concentrated to give the titlecompound as a colorless solid.

[0298] 3-(3,4-Dimethoxy-phenyl)-propylamine.

[0299] A solution of 3-(3,4-dimethoxy-phenyl)-propionamide (11.1 g, 53.0mmol) in anhydrous THF (400 ml) is slowly added to a stirred, ice-cooledsuspension of LiAlH₄ (4.02 g, 106 mmol) in anhydrous THF (170 mL). Uponcompletion of the addition, the mixture is stirred at reflux for 2 h.After cooling to 0° C., H₂O (5 mL) and NaOH 1N (5 mL) are added dropwiseto decompose the excess of hydride. The suspension is filtered andevaporated. The residue is partitioned between H₂O (40 mL) and CH₂Cl₂(100 mL). The organic layer is washed with saturated aqueous NaHCO₃ andbrine, dried over anhydrous MgSO₄, and concentrated under reducedpressure to give the title compound as a yellow oil.

[0300]2-(3,4-Dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyldropyl]-acetamide.

[0301] A solution of 3-(3,4-dimethoxy-phenyl)-propylamine (12.5 g, 64.1mmol) and TEA (10 mL, 71.8 mmol) in anhydrous THF (70 mL) is cooled to0° C. and (3,4-dimethoxy-phenyl)-acetyl chloride (13.8 g, 64.1 mmol) inTHF (28 mL) is added dropwise. After stirring at rt for 13 h undernitrogen, a saturated aqueous NaHCO₃ solution is added and the reactionmixture is extracted three times with EtOAc. The organic phase is driedover anhydrous MgSO₄, filtered and the solvent evaporated. The residueis washed with toluene and dried to give the title as a beige solid.

[0302]1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.

[0303] A mixture of2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide(6.16 g, 16.5 mmol) and POCl₃ (4.95 mL, 54.1 mmol) in anhydrousacetonitrile (185 mL) is stirred at reflux for 4 h under nitrogen. Aftercooling, the reaction mixture is evaporated and the residue is dissolvedin MeOH (125 mL). The solution is cooled to 0° C. and NaBH₄ (4.31 g, 114mmol) is added portionwise. After stirring at 0° C. for 2 h undernitrogen, the reaction mixture is poured into H₂O and extracted threetimes with CH₂Cl₂. The combined organic extracts are washed with brine,dried over anhydrous MgSO₄, filtered and concentrated to give a crudeoil. Flash chromatography (CH₂Cl₂/MeOH: 9/1) yields the title compoundas a yellow oil.

[0304] A46.1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoguinoline.

[0305] 3-(2,3-Difluoro-phenyl)-propionic Acid.

[0306] To a suspension of 2,3-difluoro-cinnamic acid (2.94 g, 16 mmol)in ethanol (100 mL) is added Pd (10% on carbon, 50 mg) and the mixtureis treated with hydrogen (7.5 bar) for 15 h. The suspension is filteredthrough celite and the solvent evaporated to provide the title compound.

[0307]1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline.

[0308] The compound is prepared from 3-(2,3-difluoro-phenyl)-propionicacid and 2-(3,4-dimethoxy-phenyl)-ethylamine according to the method ofexample A8.

Example A47

[0309] The following starting material is prepared according to themethod of example A46:

[0310] A47.1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0311] A48.1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoguinoline-7-carboxylicAcid Dimethylamide.

[0312] 2-(4-Benzyloxy-3-methoxy-phenyl)-vinylamine.

[0313] A stirred suspension of LAH (8.0 g, 0.21 mol) in THF (300 mL) iscooled in an ice bath and a solution of4-benzyloxy-3-methoxynitrostyrene (15.0 g, 52.6 mmol) in THF (300 mL) isadded dropwise. The green reaction mixture is allowed to warm to roomtemperature over 0.5 h, and is then refluxed for 4 h. The grey reactionmixture is treated successively with water (8 mL), 15% aqueous NaOH (8mL), and water (24 mL). The resulting gray suspension is stirred at 50°C. for 20 min. The resulting yellow suspension is filtered, and theresidue is washed with EtOAc. The combined filtrates are evaporated toprovide the title compound as yellow oil which is used without furtherpurification.

[0314]N-[2-(4-Benzyloxy-3-methoxy-phenyl)-vinyl]-2-(3,4-dichloro-phenyl)-acetamide.

[0315] A mixture of 3,4-dichlorophenyl acetic acid (10.6 g, 51.7 mmol)and 2-4-benzyloxyz-3-methoxy-phenyl)-vinylamine (12.1 g, 47 mmol) intoluene (100 mL) is heated at reflux in a Dean-Stark apparatus for 17 h.The reaction is allowed to cool to rt. Filtration yields the titlecompound as yellow crystals. The filtrate is heated again at reflux in aDean-Stark apparatus for 16 h, and then allowed to cool to rt.Filtration provides a second portion of the title compound as yellowcrystals. The two batches are combined and used without furtherpurification.

[0316]7-Benzyloxy-1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline.

[0317] To a suspension ofN-[2-(4-benzyloxy-3-methoxy-phenyl)-vinyl]-2-(3,4-dichloro-phenyl)-acetamide(13.3 g, 30 mmol) in CH₃CN (100 mL) at rt is added dropwisephosphoroxychloride (8.1 mL, 13.5 g, 88 mmol). The resulting whitesuspension is heated to reflux, and the resulting yellow solution isheated at reflux for 3 h. The dark yellow solution is allowed to cooland is evaporated to a yellow oil. The oil is taken up in MeOH (100 mL)and evaporated to yield an orange solid. The material is redissolved inMeOH (100 mL) and the solution is cooled to 0° C. NaBH₄ (3.61 g, 95mmol) is added in portions with gas evolution and a strong exotherm. Theresulting white suspension is stirred at rt for 16 h. The reactionmixture is partitioned between EtOAc (200 mL) and water (200 mL), andthe aqueous phase is extracted with EtOAc (3×200 mL). The combinedorganic phase is washed with water and brine, and evaporated to providethe title compound as a faint yellow oil which is used without furtherpurification.

[0318]1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-ol.

[0319] To a solution of7-benzyloxy-1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline(14.1 g, 30 mmol) in MeOH (150 mL) and 1,2-dichlorobenzene (30 mL) isadded 50% Pd on charcoal (500 mg). The reaction vessel is flushed withnitrogen and then with hydrogen at atmospheric pressure. After stirringat rt for 16 h, the reaction mixture is filtered through Hyflo, andevaporated to yield to the title compound as a beige solid which is usedwithout further purification.

[0320]1-(3,4-Dichloro-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoguinoline-2-carboxylicAcid Tert-butyl Ester.

[0321] To a solution of1-(3,4-dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-ol(9.6 g, 28 mmol) in isopropanol (30 mL) is added dropwise 1 M aqueousNaOH (30 mL) and di-tert-butyl-dicarbonate (6.7 g, 30.8 mmol). Theresulting brown solution is stirred at rt for 30 min, and the resultingyellow solution is partioned between EtOAc (50 mL) and water (50 mL).The organic phase is washed successively with water and with brine, andis evaporated to provide the title compound as yellow oil, which is usedwithout further purification.

[0322]1-(3,4-Dichloro-benzyl)-6-methoxy-7-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylicAcid Tert-butyl Ester.

[0323] To a solution of1-(3,4-dichloro-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (12 g, 27 mmol) in CH₂Cl₂ (100 mL) is added Et₃N(3.8 mL, 27 mmol). The reaction mixture is cooled to 0° C. andtrifluoromethanesulfonic anhydride (4.45 mL, 27 mmol) is added. Theresulting yellow solution is stirred at rt 30 min, and is poured ontoaqueous saturated NaHCO₃ (100 mL). The aqueous phase is extracted withCH₂Cl₂ (2×100 mL), and the combined organic phases are dried (MgSO4),filtered and evaporated to provide the title compound as yellow oil.Purification is achieved by crystallization from MeOH. The evaporatedmother liquor furnishes additional material upon silica gelchromatography (heptane:Et2O, 9:1).

[0324]7-Cyano-1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoguinoline-2-carboxylicAcid Tert-butyl Ester.

[0325] A solution of1-(3,4-dichloro-benzyl)-6-methoxy-7-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (10 g, 17 mmol) in DMF (15 mL) standing overfreshly dried 4 A molecular sieves is deoxygenated by bubbling withargon for 20 min. This solution is added to a deoxygenated suspension ofzinc cyanide (4.6 g, 34 mmol) in DMF (15 mL) under argon. The resultinglight brown suspension is placed in a 120° C. oil bath.Tetrakis-(triphenylphosphine)-palladium (1.0 g) is added, and the brownreaction mixture is stirred at 120° C. for 2 h. The reaction mixture iscooled to rt, and partitioned between EtOAc and saturated aqueousNaHCO₃. The mixture is filtered through Hyflo. The aqueous phase isextracted with EtOAc (3×40 mL). The combined organic phases areextracted with brine, dried over MgSO₄, filtered, and evaporated. Theresulting yellow oil partially solidifies. The mixture is filtered andwashed with Et₂O to provide the title compound as white crystals.Evaporation of the filtrate and silica gel chromatography(EtOAc:heptane, 1:4) provides additional title compound as whitecrystals.

[0326]1-(3,4-Dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2,7-dicarboxylicAcid 2-tert-butyl Ester.

[0327] To a solution of7-cyano-1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (3.60 g, 8.06 mmol) in benzyl alcohol (10 mL) isadded KOH (3.00 g), and the reaction mixture is stirred at 160° C. for0.5 h. The reaction mixture is allowed to cool to rt and is acidifiedwith 2 M aqueous HCl. The reaction mixture is partitioned with EtOAc(3×20 mL). The combined organic phases are washed with brine, dried overMgSO₄, filtered, and evaporated to yield a yellow oil. Chromatographyover silica gel with CH₂Cl₂:MeOH 19:1 and then with MeOH provides thetitle compound as yellow solid.

[0328]1-(3,4-Dichloro-benzyl)-7-dimethylcarbamoyl-6-methoxy-3,4-dihydro-1H-isoguinoline-2-carboxylicAcid Tert-butyl Ester.

[0329] To a solution of1-(3,4-dichloro-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinoline-2,7-dicarboxylicacid 2-tert-butyl ester (1.0 g, 2.1 mmol) in CH₂Cl₂ (10 mL) is addeddimethylamine hydrochloride (0.35 g, 4.3 mmol), HOBt (65 mg, 0.43 mmo),DMAP (52 mg, 0.43 mmol), and EDC hydrochloride (493 mg, 2.6 mmol). Thereaction mixture was stirred at rt for 16 h. The fine yellow suspensionis diluted with CH₂Cl₂ (10 mL), and is washed with 1 M aqueous HCl andsaturated aqueous NaHCO₃. The organic phase is dried over MgSO₄,filtered and evaporated to give the title compound.

[0330] 1-(3,4-Dichloro-benzyl)6-methoxy-1,2,3,4-tetrahydro-isoguinoline-7-carboxylic AcidDimethylamide.

[0331] A solution of1-(3,4-dichloro-benzyl)-7-dimethylcarbamoyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.0 g, 2.0 mmol) in 4 M HCl in dioxane is stirredat 0° C. for 1 h. The reaction mixture is evaporated to provide thetitle compound as a white solid.

Examples A49-A50

[0332] The following starting materials are prepared according to themethod of example A48:

[0333] A49.1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carboxylicacid methylamide

[0334] A50.1-(3,4-Dichloro-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-carboxylicacid propylamide

Examples A51-A52

[0335] Enantiomerically pure starting materials are prepared accordingto the method of Polniaszek R. P. et al., J. Am. Chem. Soc. (1989) 111,4859-4863.

[0336] A51.(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0337] A52.(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

[0338] Preparation of Intermediates.

Example B

[0339] B1. (2-Bromo-ethyl)-carbamic Acid Tert-butyl Ester.

[0340] To 1 N aqueous NaOH (200 mL) is added to MeOH (400 mL) and theresulting solution is cooled to 20° C. 2-Bromoethylamine hydrobromide(25.0 g, 122 mmol) is added in a single portion, followed di-tert-butyldicarbonate (26.6 g, 122 mmol). The reaction mixture is stirred for 2.5h. The MeOH is removed on a rotary evaporator, and the aqueoussuspension is extracted with CH₂Cl₂ (2×175 mL). The combined organicphases are extracted with 5% aqueous citric acid (300 mL), dried overMgSO₄, filtered, and evaporated to provide the title compound.

[0341] B2. (3-Chloro-propyl)-carbamic Acid Tert-butyl Ester

[0342] This material is prepared analogously to example B1 from3-chloropropylamine.

[0343] Preparation of Intermediates.

Example C

[0344] C1. 4-Amino-2-methylquinoline.

[0345] This material is commercially available.

[0346] C2. 4-Amino-pyridine.

[0347] This material is commercially available.

[0348] C3. 4-Amino-quinoline.

[0349] Prepared from commercial 4-nitroquinoline N-oxide according tothe method described in Shinkai H et al., “4-Aminoquinolines: NovelNociceptin Antagonists with Analgesic Activity”, J. Med. Chem. (2000)43, 4667-4677.

[0350] C4. 4-Amino-6,7,8,9-tetrahydro-quinoline.

[0351] 6,7,8,9-Tetrahydro-quinoline-N-oxide.

[0352] A solution of 5,6,7,8-tetrahydroquinoline (2.66 mL, 20 mmol) inTHF (125 mL) is cooled to 0° C. and a solution of m-chloroperbenzoicacid (3.8 g, 22 mmol) in THF (25 mL) is added. After 0.5 h the mixtureis evaporated in vacuo and redissolved in CH₂Cl₂ (75 mL). The solutionis washed with NaOH (1 M, 20 mL) and citric acid (10%, 20 mL), dried andevaporated to provide the title compound.

[0353] 4-Nitro-6,7,8,9-tetrahydro-quinoline-N-oxide.

[0354] 5,6,7,8-Tetrahydroquinoline-N-oxide (298 mg, 2 mmol) is treatedwith a cooled mixture of HNO₃ (100%, 0.5 mL) and H₂SO₄ (98%, 0.7 mL).The mixture is heated to 80° C. for 2 h, poured into ice (100 g) andextracted with CH₂Cl₂ (30 mL). The organic phase is dreid and evaporatedto provide the title compound.

[0355] 4-Amino-6,7,8,9-tetrahydro-quinoline.

[0356] Prepared from 4-nitro-6,7,8,9-tetrahydro-quinoline-N-oxideaccording to the method of example C3.

[0357] C5. 4-Amino-7-methyl-[1,8]-naphthyridine.

[0358] Prepared according to the method described in Barlin G B, Tan WL, “Potential Antimalarials. I 1,8-naphthyridines”, Aust J Chem (1984)37, 1065-1073. Radivov R, Haimova M, Simova E “Synthesis of4-Amino-3-Pyridiyl and 4-Amino-5-Pyrimidyl Aryl Ketones and RelatedCompounds via an ortho-Lithiation Reaction”, Synthesis (1986), 886-891.

[0359] C6. Quinoline-4-carboxylic Acid.

[0360] This material is commercially available.

[0361] C7. 2-Methyl-quinoline-4-carboxylic Acid.

[0362] This material is prepared by reaction of isatin with acetoneaccording to the method described in Brasyunas V B et al., “Synthesis ofQuinoline-4-carboxylic acid and its derivatives”, Chem. Heterocycl.Compd. (engi. Transl.) (1988) 670-673.

[0363] C8. 2-(Benzyl-methyl-amino)-isonicotinic Acid.

[0364] A mixture of 2-chloro-pyridine-4-carboxylic acid (300 mg, 1.9mmol), benzylmethylamine (230 mg, 1.9 mmol) and triethylamine (192 mg,1.9 mmol) is heated to 120° C. for 12 h. The residue is dissolved inCH₂Cl₂ (30 mL) and extracted with 1M NaOH (3×5 mL). The aqueous phase isadjusted to pH 2 and extracted with EtOAc (6×5 mL). The organic phasesare combined, dried (MgSO₄), and evaporated to provide the titlecompound.

[0365] C9. 2-(Benzyl-methyl-amino)-6-methyl-isonicotinic Acid.

[0366] This material is prepared by reaction of2-chloro-6-methyl-pyridine-4-carboxylic acid with benzylmethylamineanalogously to example C8.

[0367] C10. 2-(Methyl-phenyl-amino)-isonicotinic Acid.

[0368] This material is prepared by reaction of2-chloro-pyridine-4-carboxylic acid with N-methylaniline analogously toexample C8.

[0369] C11. 2-Pyrrolidin-1-yl-isonicotinic Acid.

[0370] This material is prepared by reaction of2-chloro-pyridine-4-carboxylic acid with pyrrolidine analogously toexample C8.

[0371] Preparation of Intermediates.

Example D

[0372] D1. 1-(2-Chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea.

[0373] To a solution of 4-amino-2-methylquinoline (example C1, 12.6 g,80 mmol) in THF (480 mL) is added 2-chloroethylisocyanate (10.2 mL, 120mmol) at rt. The reaction mixture is stirred for 40 h at rt. MeOH (100mL) is added, and stirring is continued an additional hour. The reactionmixture is evaporated and the residue is taken up in CH₂Cl₂. The organicphase is shaken with 1 N HCl (250 mL), and the resulting precipitate iscollected by filtration. The solid is washed with CH₂Cl₂ (100 mL),saturated NaHCO₃ (2×100 mL), and with water (4×100 mL). The resultingsolid is dried under HV at rt for 14 h to provide the title compound.

[0374] D2. 1-(3-Chloro-propyl)-3-(2-methyl-quinolin-4-yl)-urea.

[0375] Analogously to method D1 the title compound is prepared from4-amino-2-methylquinoline (example C1) and 3-chloropropylisocyanate.

[0376] D3. 1-(2-Chloro-ethyl)-3-(quinolin-4-yl)-urea.

[0377] Analogously to method D1 the title compound is prepared from4-amino-2-quinoline (example C3) and 2-chloroethylisocyanate.

[0378] D4. 1-(3-Chloro-propyl)-3-(quinolin-yl)-urea.

[0379] Analogously to method D1 the title compound is prepared from4-amino-2-quinoline (example C3) and 3-chloropropylisocyanate.

[0380] D5. 1-(2-Chloro-ethyl)-3-(pyridin-4-yl)-urea.

[0381] Analogously to method D1 the title compound is prepared from4-amino-pyridine (example C2) and 2-chloroethylisocyanate.

[0382] D6. 1-(2-Chloro-ethyl)-3-(7-methyl-[1,8]-naphthyridin-4-yl)-urea.

[0383] Analogously to method D1 the title compound is prepared from4-amino-7-methyl-[1,8]-naphthyridine (example C5) and2-chloroethylisocyanate.

[0384] Preparation of Final Products

Example 1

[0385]1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea.

[0386] To a solution of1-(4-fluoro-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline(example A1, 50 mg, 0.16 mmol) in anhydrous THF (2.5 mL) is added1-(2-chloro-ethyl)-3-2-methyl-quinolin-4-yl)-urea (example D1, 43.8 mg,0.16 mmol), TEA (34.6 μL, 0.25 mmol) and NaI (2.5 mg, 0.017 mmol). Themixture is stirred at 75° C. for five days in a sealed flask. Thereaction mixture is evaporated, and the residue is purified bypreparative HPLC to provide the title compound.

[0387] LC-MS (MeCN/H₂O, 1:1) t_(R)=0.93 min, m/z=529.3 (M+1)

Examples 2-6

[0388] The additional examples set out in the following table areprepared starting from examples A1 to A4 and examples D1 or D3 using themethod of example 1. Exam- ple [M + No Example t_(R) H]⁺ 21-{2-[1-(3,4-Difluoro- 0.97 547.30 benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 31-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8- 1.05 559.70dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]- ethyl}-3-(2-methyl-quinolin-4-yl)-urea 4 1-{2-[1-(3,4-Difluoro-benzyl)-6,8- 0.80 533.30dimethoxy-3,4-dihydro-1H- isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea5 1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,8 1.13 545.24-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]- ethyl}-3-quinolin-4-yl-urea6 1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4- 0.78 515.30dihydro-1H-isoquinolin-2-yl]-ethyl}-3- quinolin-4-yl-urea

Example 7

[0389]1-{2-(4-Fluoro-phenyl)ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinoline-4-yl)-urea.

[0390]1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-1,2,3,4,-tetrahydro-isoquinoline(example A5, 100 mg, 0.317 mmol) is dissolved in anhydrous THF (3.0 mL),1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (example D1, 83.6 mg,0.317 mmol), TEA (66.2 μL, 0.475 mmol) and NaI (4.8 mg, 0.032 mmol) areadded. The mixture is stirred at 75° C. for five days in a sealed flask.The reaction mixture is evaporated, and the residue is purified bypreparative HPLC to provide the title compound.

[0391] LC-MS (MeCN/H₂O, 1:1) t_(R)=1.11 min, m/z=543.5 (M+1)

Examples 8-9

[0392] The additional examples set out in the following table areprepared starting from examples A5 to A7 and examples D1 or D3 using themethod of example 7. Exam- ple No Example t_(R) [M + H]⁺ 81-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8- 1.16 561.34dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 91-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8- 1.15 547.32dimethoxy-3,4-dihydro-1H-isoquinolin-2- y}-ethyl)-3-quinolin-4-yl-urea10 1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8- 1.16 561.33dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 111-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8- 1.16 547.31dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl}-ethyl)-3-quinolin-4-yl-urea12 1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8- 1.15 529.30dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl}-ethyl)-3-quinolin-4-yl-urea

Example 13

[0393]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea.

[0394] To a solution of1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline(example A31, 0.16 g, 0.50 mmol) in THF (2 mL) is added1-(2-chloroethyl)-3-(2-methylquinolin-yl)-urea (example D1, 0.18 g, 0.60mmol), solid NaHCO₃ (50 mg, 0.6 mmol) and NaI (15 mg, 0.1 mmol). Themixture is stirred at 70° C. in a sealed flask for 5 days. The mixtureis evaporated, and the residue is purified by preparative HPLC toprovide the title compound.

[0395] LC-MS (MeCN/H₂O, 1:1) t_(R)=1.10 min, m/z=529.19 (M+1)

Examples 14-105

[0396] The additional examples set out in the following table areprepared starting from examples A1 to A52 and examples D1 to D5 usingthe method of example 13. Example No Example t_(R) [M + H]⁺ 141-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy- 1.01 585.191,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 151-(2-{1-[(E)-2-(2,4-Difluoro-phenyl)-vinyl]-6,7- 1.13 559.31dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 161-(2-{1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7- 1.13 559.30dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 171-(2-{1-[2-(2,3-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.33dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 181-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.34dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 191-(2-{1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7- 1.18 661.30dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 201-(2-{1-[2-(2,5-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.32dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 211-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,7- 1.14 561.32dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 221-(2-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6,7- 1.09 585.37dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 231-(2-{1-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7- 1.19 661.30dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 241-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,7-dimethoxy- 1.14 543.323,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea25 1-(2-{6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]- 1.13 555.363,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea26 1-(2-{6,7-Dimethoxy-1-[2-(3-methoxy-phenyl)-ethyl]- 1.13 555.363,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea27 1-(2-{6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]- 1.13 555.373,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl- quinolin-4-yl)-urea28 1-(2-{6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)- 1.17 593.35ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 291-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.11 525.22isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)- urea 301-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.07 461.12isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 311-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.11 511.07isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 321-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.11 539.26isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)- urea 331-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H- 1.10 525.18isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea 341-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy- 1.14 555.213,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl- quinolin-4-yl)-urea35 1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy- 0.99 491.073,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl- urea 361-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy- 1.06 541.073,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4- yl-urea 371-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)- 1.03 387.12ethyl]-3-pyridin-4-yl-urea 381-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)- 1.10 437.08ethyl]-3-quinolin-4-yl-urea 391-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.09 511.17isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)- urea 401-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 0.98 447.10isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 411-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.07 497.08isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 421-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H- 1.06 417.09isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 431-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H- 1.11 467.12isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 441-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4- 1.10 497.10dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl- urea 451-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4- 1.12 547.14dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl- urea 461-[2-(6,7-Dimethoxy-1-phenoxymethyl-3,4-dihydro- 0.98 463.091H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 471-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.08 525.25isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)- urea 481-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H- 1.04 511.17isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea 491-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.04 507.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 501-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.10 557.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 511-{2-[1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-3,4- 1.12 579.26dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 521-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4- 1.04 483.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 531-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4- 1.10 533.04dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 541-{2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4- 1.10 587.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 551-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 0.94 507.16dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 561-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.01 557.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 571-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 0.83 561.30dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea 581-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 571.21dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 591-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.08 507.16dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 601-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 557.18dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 611-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4- 1.02 477.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 621-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4- 1.08 527.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 631-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy- 1.11 559.333,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea64 1-{2-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7- 1.15 597.33dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 651-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4- 1.09 481.04dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 661-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4- 1.11 531.08dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 671-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1.01 465.111H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 681-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1.09 515.061H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 691-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4- 1.00 537.17dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 701-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4- 1.08 587.09dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 711-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4- 1.12 601.29dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 721-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4- 0.96 537.09dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 731-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4- 1.03 587.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 741-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4- 1.00 477.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 751-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4- 1.08 527.10dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 761-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4- 0.99 477.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 771-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4- 1.07 527.11dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 781-{3-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4- 1.09 547.18dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl- urea 791-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.03 585.20dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl- quinolin-4-yl)-urea 801-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4- 1.01 571.19dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl- urea 811-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 585.21dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl- quinolin-4-yl)-urea 821-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4- 1.11 571.21dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl- urea 831-{3-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro- 1.07 529.221H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea 841-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H- 0.99 491.09[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-pyridin-4- yl-urea 851-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H- 1.07 541.08[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-quinolin- 4-yl-urea 861-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro- 1.00 505.076H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3- pyridin-4-yl-urea 871-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro- 1.06 555.086H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3- quinolin-4-yl-urea 881-[2-(1-Benzhydryl-5,8-dimethoxy-3,4-dihydro-1H- 1.14 573.11isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 891-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H- 1.10 523.07isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 901-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H- 1.12 573.08isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 911-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H- 1.09 447.15isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 921-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H- 1.13 497.09isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 931-{2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4- 1.11 557.08dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 941-{2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4- 1.14 557.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 951-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4- 1.08 475.12dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl- urea 961-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4- 1.11 525.09dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl- urea 971-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4- 1.29 585.29dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3- quinolin-4-yl-urea98 1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy- 1.05 571.353,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea99 1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy- 1.01 557.143,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4- yl-urea 1001-{2-[(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4- 0.77 529.08dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 1011-{2-[7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6- 0.82 647.1methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1021-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4- 0.77 541.13dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl- quinolin-4-yl)-urea 1031-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2- 0.78 606.13methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid methylamide 1041-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2- 0.82 634.04methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid propylamide 1051-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2- 0.78 620.00methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid dimethylamide

Example 106

[0397]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea.

[0398] 106.1.{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicAcid Tert-butyl Ester.

[0399] To a solution of1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline(example A31, 1.05 g, 3.5 mmol) in THF (40 mL) is added(2-bromo-ethyl)-carbamic acid tert-butyl ester (example B1, 0.94 g, 4.2mmol) and DIPEA. The reaction mixture is stirred at 70° C. in a sealedflask for 5 days. After cooling to rt, the reaction mixture isevaporated to dryness, and the residue is purified by preparative HPLCto provide the title compound.

[0400] 106.2.1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1,8]naphthyridin-4-yl)-urea.

[0401] To a stirred solution of{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in glacial AcOH(1 mL) is added conc. HCl (0.1 mL). After 5 min, the reaction mixture ispartitioned with CHCl₃ (20 mL) and 1 N NaOH (15 mL). The organic phaseis evaporated. The residue is taken up in DMSO (2 mL) and treated withCDI (0.2 g, 0.6 mmol, 1.2 eq). The reaction mixture is stirred at rt for3 h, and then 4-amino-7-methyl-[1,8]-naphthyridine (example C5, 0.19 g,0.6 mmol) is added. To the resulting solution is added in a singleportion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reaction mixture isstirred at rt for 30 min, then H₂O (0.4 mL) is added. The reactionmixture is evaporated and the residue purified by preparative HPLC toprovide the title compound.

[0402] LC-MS (MeCN/H₂O, 1:1) t_(R)=0.92 min, m/z=530.3 (M+1)

Example 107

[0403]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea.

[0404] To a stirred solution of{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in glacial AcOH(1 mL) is added conc. HCl (0.1 mL). After 5 min, the reaction mixture ispartitioned between CHCl₃ (20 mL) and 1 N NaOH (15 mL). The organicphase is evaporated. The residue is taken up in DMSO (2 mL) and treatedwith CDI (0.2 g, 0.6 mmol, 1.2 eq). The reaction mixture is stirred atrt for 3 h, and then 4-amino-5,6,7,8-tetrahydroquinoline (example C4,0.19 g, 0.6 mmol) is added. To the resulting solution is added in asingle portion NaHMDS (2 M in THF, 1.25 mL, 2.5 mmol). The reactionmixture is stirred at rt for 30 min, then H₂O (0.4 mL) is added. Thereaction mixture is evaporated and the residue purified by preparativeHPLC to provide the title compound.

[0405] LC-MS (MeCN/H₂O, 1:1) t_(R)=0.92 min, m/z=519.3 (M+1)

Example 108

[0406]1-[2-(Benzyl-methyl-amino)-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea.

[0407] 108.1 Benzyl-(4-isocyanato-pyridin-2-yl)-methyl-amine.

[0408] To a solution of 2-(benzyl-methyl-amino)-isonicotinic acid(example C8, 780 mg, 3.2 mmol) in DMF (10 mL) at 0° C. is addedtriethylamine (360 mg, 3.5 mmol). After 5 minutes DPPA (975 mg, 3.5mmol) is added, and stirring is continued for 2 h at 0° C. and 12 h at20° C. The reaction is quenched with ice (10 g) and extracted with Et₂O(6×30 mL). The combined organic phases are washed successively withsaturated NaHCO₃ (2×15 mL) and water (2×10 mL), and are evaporatedwithout heating in vacuo. The residue is dissolved in dry toluene (16mL) and heated to reflux for 2 h. The resulting solution is carriedforward without further isolation of the title compound.

[0409] 108.21-[2-(Benzyl-methyl-amino)-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea.

[0410] To a stirred solution of{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester (example 106.1, 0.22 g, 0.5 mmol) in CH₂Cl₂ (1 mL)is added TFA (1 mL). After 2 h, the reaction mixture evaporated andpartitioned between CH₂Cl₂ (20 mL) and 1 N NaOH (15 mL). The organicphase is dried (MgSO₄) and evaporated. The residue is dissolved inCH₂Cl₂ (2 mL) and added to a freshly prepared solution ofbenzyl-(4-isocyanato-pyridin-2-ylmethyl-amine (example 108.1, 95.7 mg,0.40 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C.Evaporation of the solvent and purification by HPLC provides the titlecompound.

[0411] LC-MS (MeCN/H₂O, 1:1) t_(R)=0.73 min, m/z=584.3 (M+1)

Examples 109-111

[0412] The additional examples set out in the following table areprepared starting from example 106.1 and examples C9 to C11 using themethod of example 108. Example No Example t_(R) [M + H]⁺ 1091-[2-(Benzyl-methyl-amino)-6- 0.76 598.43 methyl-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)- 6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea 110 1-{2-[1-(4-Fluoro-benzyl)-6,7- 0.80570.10 dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl]-ethyl}-3-[2-(methyl-phenyl- amino)-pyridin-4-yl]-urea 111 1-{2-[1-(4-Fluoro-benzyl)-0.77 534.09 6,7-dimethoxy-3,4-dihydro- 1H-isoquinolin-2-yl]-ethyl}-3-(2-pyrrolidin-1-yl- pyridin-4-yl)-urea

Example 112

[0413]1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methylamino-1-yl-pyridin-4-yl)-urea.

[0414] To a mixture of1-[2-(benzyl-methyl-amino)pyridin-4-yl]-3{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea(example 108, 0.12 g, 0.2 mmol) and Pd (10% on carbon, 20 mg) in MeOH(10 mL) is added HCl (1N, 0.2 mL). A stream of hydrogen is passedthrough the solution for 0.5 h and the solution is stirred under anatmosphere of hydrogen for 15 h. The solution is filtered and evaporatedto provide the title compound.

[0415] LC-MS (MeCN/H₂O, 1:1) t_(R)=0.77 min, m/z=534.09 (M+1)

Example 113.

[0416] (Quinolin-4-yl)-carbamic acid2-(6.7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylEster.

[0417] 113.1.2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanol.

[0418] A solution of6,7-dimethoxy-1-phenethyl-1,2,3,4-tetrahydro-isoquinoline (example A21,59.5 mg, 0.2 mmol) and 2-bromoethanol (28.3 μL, 0.4 mmol) intetrahydropyran (3 mL) is treated with DIPEA (68 μL, 0.4 mmol), and thereaction mixture is heated at 90° C. in a sealed flask for 5 days. Thereaction is mixture evaporated to dryness, and the residue is purifiedby preparative HPLC, to provide the title compound.

[0419] 113.2. (Quinolin-4-yl)-carbamic Acid2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethylEster.

[0420] To a solution of2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanol(example 113.1, 29.7 mg, 0.087 mmol) in THF (1 mL) is added CDI (28.2mg, 0.174 mmol, 2.0 eq). The reaction mixture is stirred at rt for 3 h,and then 4-amino-quinoline (example C3, 14 mg, 0.1 mmol) is added. Tothe resulting solution is added in a single portion NaHMDS (2 M in THF,218 μL, 0.44 mmol). The reaction mixture is stirred at rt for 30 min,then H₂O/AcOH (9:1, 0.4 mL) is added. The reaction mixture is evaporatedand the residue purified by preparative HPLC to provide the titlecompound.

[0421] LC-MS (MeCN/H₂O, 1:1) t_(R)=1.17 min, m/z=512.19 (M+1)

Examples 114-120

[0422] The additional examples set out in the following table areprepared starting from examples A1 to A52 and examples C1 to C3 usingthe method of example 113. Example No Example t_(R) [M + H]⁺ 114Quinolin-4-yl-carbamic acid 2-(1-benzyl-6,7- 1.09 498.19dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester 115Quinolin-4-yl-carbamic acid 2-[1-(4-fluoro-benzyl)- 1.12 516.166,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl ester 116Quinolin-4-yl-carbamic acid 3-(1-benzyl-6,7- 1.05 512.15dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester 117Quinolin-4-yl-carbamic acid 3-(6,7-dimethoxy-1- 1.10 526.19phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester 118Quinolin-4-yl-carbamic acid 3-[1-(3,4-difluoro- 1.10 548.18benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl]-propyl ester 119Quinolin-4-yl-carbamic acid 3-[1-(3,4-dimethoxy- 1.10 572.25benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2- yl]-propyl ester 120Quinolin-4-yl-carbamic acid 3-[1-(4-fluoro-benzyl)- 1.08 530.126,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]- propyl ester

Example 121

[0423] In Vitro Biological Characterization

[0424] The inhibitory activity of the compounds of general formula 1 onthe actions of urotensin II can be demonstrated using the testprocedures described hereinafter:

[0425] 1) Inhibition of Human [125I]-urotensin II Binding to aRhabdomyosarcoma Cell Line

[0426] Whole cell binding of human [¹²⁵I]-urotensin II is performedusing human-derived TE-671 rhabdomyosarcoma cells (Deutsche Sammlung vonMikroorganismen und Zellkulturen, cell line #ACC-263), by methodsadapted from a whole cell endothelin binding assay (Breu V et al., Invitro characterization of Ro-46-2005, a novel synthetic non-peptideantagonist of ET_(A) and ET_(B) receptors. FEBS Lett. 1993, 334,210-214).

[0427] The assay is performed in 250 mL Dubecco's modified eagle medium,pH 7.4 (GIBCO BRL, CatNo 31885-023), including 25 mM HEPES (Fluka, CatNo05473), 1.0% DMSO (Fluka, CatNo 41644) and 0.5% (w/v) BSA Fraction V(Fluka, CatNo 05473) in polypropylene microtiter plates (Nunc, CatNo442587). 300,000 suspended cells are incubated with gentle shaking for 4h at 20° C. with 20 μM human [¹²⁵I]Urotensin II (Anawa Trading SA,Wangen, Switzerland, 2130 Ci/mmol) and increasing concentrations ofunlabeled antagonist. Minimum and maximum binding are derived fromsamples with and without 100 nM unlabelled U-II, respectively. After the4 h incubation period, the cells are filtered onto GF/C filter plates(Packard, CatNo 6005174). The filter plates are dried, and then 50 μLscintillation cocktail (Packard, MicroScint 20, CatNo 6013621) is addedto each well. The filter plates are counted in a microplate counter(Packard Bioscience, TopCount NXT).

[0428] All test compounds are dissolved and diluted in 100% DMSO. Aten-fold dilution into assay buffer is performed prior to addition tothe assay. The final concentration of DMSO in the assay is 1.0/, whichis found not to interfere with the binding. IC50 values are defined asthe concentration of antagonist inhibiting 50% of the specific bindingof [¹²⁵I]human U-IY. Specific binding is the difference between maximumbinding and minimum binding, as described above. An IC50 value of 0.206nM is found for unlabeled human U-II. The compounds of the invention arefound to have IC50 values ranging from 1 to 10000 nM in this assay.Specific examples have IC50's given in the following table. Example IC50[nM] 20 67 22 63 29 125 58 550

[0429] 2) Inhibition of Human Urotensin II-Induced Contractions ofIsolated Rat Aortic arch:

[0430] Adult Wistar rats are anesthetized (CO₂ inhalation) andexsanguinated. The aortic arch is excised, dissected and cut in 3 ringsof 3 mm, ring #1 being the more proximal and ring #3 being the moredistal. Each ring is suspended in a 10 mL isolated organ bath filledwith Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO₄ 1.2,KH₂PO₄ 1.5, NaHCO₃ 25, CaCl₂ 2.5, glucose 10; pH 7.4) kept at 37° C. andgassed with 95% O₂ and 5% CO₂. The rings are connected to forcetransducers and isometric tension is recorded (EMKA Technologies SA,Paris, France). The rings are stretched to a resting tension of 3 g.Cumulative doses of human urotensin II (10⁻¹¹ M to 10⁻⁶ M) are addedafter a 20 min incubation with the test compound or its vehicle (DMSO,10 EL). An EC50 value of 1.09±0.1 nM is found for unlabeled human U-II.The functional inhibitory potency of the test compound is assessed bycalculating the pD₂′ according to the formula: pD₂′=Log (CR-1)-Log [B],where CR is the ratio of the maximal effect without/with antagonist and[B] the concentration of the antagonist. Specific examples have pD2′values given in the following table: Example pD2′ 29 5.23 93 5.45

1. Compounds of the general formula 1,

wherein X represents —CH₂—, CH₂CH₂—, —C(CH₃)₂; Y represents oxygen, NH; n represents the numbers 1 or 2; Z represents quinolin-4-yl which may be mono-substituted with lower alkyl in the positions 2, 6, or 8, or di-substituted with lower alkyl in the positions 2, 6 or 2,8; [1,8]naphthyridin-4-yl which may be substituted in position 7 with lower alkyl; pyridin-4-yl which may be substituted in position 2 with R⁷R⁸N— and additionally in position 6 with hydrogen or lower alkyl; R¹ represents naphthalen-1-yl; naphthalen-2-yl; benzo[1,3]dioxol-5-yl; benzyl, or mono-, di-, or tri-substituted benzyl substituted in the phenyl ring independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano; phenyl, or mono-, di- or tri-substituted phenyl, substituted independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano; R² represents hydrogen, lower alkyl, aryl or forms with R¹ a styryl group of E or Z geometry, whereby the phenyl ring in the styryl group may be mono-, di- or tri-substituted phenyl, substituted independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano; R³, R⁴, R⁵ and R⁶ independently represent hydrogen, cyano, hydroxy, lower alkyloxy, aralkyloxy, lower alkenyloxy, and R⁵ additionally represents R⁷R⁸NCO; R⁴ and R⁵ together may form with the phenyl ring a five- or a six-membered ring containing one or two oxygen atoms; R⁷ and R⁸ independently represent hydrogen, lower alkyl, aryl, aralkyl, or together with the N form a pyrrolidine, piperidine, or morpholine ring; and optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates; as well as their pharmaceutically acceptable salts, solvent complexes, and morphological forms.
 2. Compounds of general formula 2,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Z, and n have the meaning given in general formula 1 above.
 3. Compounds of general formula 3,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and Z have the meaning given in general formula 1 above.
 4. Compounds of general formula 4,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given in general formula 1 above.
 5. Compounds of general formula 5,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given in general formula 1 above.
 6. Compounds of general formula 6,

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Z, and n have the meaning given in general formula 1 above.
 7. Compounds of general formula 7,

wherein R¹, R³, R⁴, R⁵, R⁶, X, Y, Z, and n have the meaning given in general formula 1 above.
 8. Compounds of general formula 8,

wherein Ph is phenyl; mono-, di- or tri-substituted phenyl, substituted independently with hydrogen, lower alkyl, lower alkyloxy, trifluoromethyl, halogen, or cyano; R³, R⁴, R⁵, R⁶, X, Y, Z, and n have the meaning given in general formula 1 above.
 9. Compounds of general formula 9,

wherein R¹, R², X, Y, Z, and n have the meaning given in general formula 1 above.
 10. Compounds of general formula 10,

wherein R¹, R², X, Y, Z, and n have the meaning given in general formula 1 above.
 11. Compounds of general formula 11,

wherein R¹, R², X, Y. Z, and n have the meaning given in general formula 1 above.
 12. Compounds of general formula 12,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and n have the meaning given in general formula
 1. 13. Compounds of general formula 13,

wherein R¹, R², R³, R⁴, R⁵, R⁶, X, Y, and n have the meaning given in general formula
 1. 14. Compounds of general formula 14,

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, Y, and n have the meaning given in general formula
 1. 15. Compounds of general formula 15,

wherein the 1 position of the 1,2,3,4-tetrahydroisoquinoline ring system has the R absolute stereochemical configuration; R¹, R², R³, R⁴, R⁵, R⁶, X, Z, and n have the meaning given in general formula
 1. 16. Compounds of general formula 16,

wherein R³, R⁴, R⁵, and R⁶ are independently hydrogen or lower alkyloxy; R¹, R², and Z have the meaning given in general formula
 1. 17. The compounds according to any one of claims 1 to 16 1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3-Fluoro-4-methoxy-benzyl 6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3,4-Difluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3-Fluoro methoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(4-Fluoro-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-(2-{1-[2-(4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea 1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea 1-(2-{1-[2-4-Fluoro-phenyl)-ethyl]-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-quinolin-4-yl-urea 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[(E)-2-(2,4-Difluoro-phenyl)vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[(E)-2-(2,5-Difluoro-phenyl)-vinyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(2,3-Dfluoro-phenylyethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(2,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolinyl)-urea 1-(2-{1-[2-(2,5-Bis-trifluoromethyl-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2(2,5-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl) -3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(3,4-Difluoro-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(3,4-Dimethoxy-phenyl)-ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(3,5-Bis-trifluoromethyl-phenyl ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{1-[2-(4-Fluoro-phenyl)ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{6,7-Dimethoxy-1-[2-(2-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolinyl)-urea 1-(2-{6,7-Dimethoxy-1-[2-3-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{6,7-Dimethoxy-1-[2-(4-methoxy-phenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-(2-{6,7-Dimethoxy-1-[2-(4-trifluoromethyl-phenyl)ethyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-3-(2-methyl-quinolin-4-yl)-urea 1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethy]-3-(2-methyl-quinolin-4-yl)-urea 1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-pyridin-4-yl-urea 1-[2-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[3-6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea 1-[3-(6,7-Dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea 1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea 1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-pyridin-4-yl-urea 1-[2-(1-Benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 1-[2-1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea 1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 1-[2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 1-[2-1-Benzyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-ylyethyl]-3-pyridin-4-yl-urea 1-[2-(6,7-Dimethoxy-1-naphthalen-2-ylmethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(6,7-Dimethoxy-1-phenoxymethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-(2-methyl-quinolin-4-yl)-urea 1-[3-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-3-quinolin-4-yl-urea 1-{2-[1-2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(2,6-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3-Fluoro-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3-Fluoro-5-trifluoromethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(2,3,4-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolinyl)-urea 1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridinyl-urea 1-{2-[6,7-Dimethoxy-1-(3,4,5-trimethoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(3-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(4-methoxy-benzyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{3-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea 1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{3-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea 1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{3-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea 1-{3-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3-quinolin-4-yl-urea 1-{2-[5-(3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[5-3,4-Dimethoxy-benzyl)-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-6-yl]-ethyl}-3-quinolin-yl-urea 1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[6-(3,4-Dimethoxy-benzyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinolin-7-yl]-ethyl}-3-quinolin-4-yl-urea 1-[2-(1-Benzhydryl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 1-[2-(1-Benzhydryl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-quinolin-4-yl-urea 1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-3-pyridin-4-yl-urea 1-[2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-quinolin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-pyridin-4-yl-urea 1-{2-[6,7-Dimethoxy-1-(1-phenyl-propyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-S4-yl)-urea 1-{2-[(R)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-quinolin-4-yl-urea 1-{2-[(R)-1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[7-Benzyloxy-1-(3,4-dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-{2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methyl-quinolin-4-yl)-urea 1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid methylamide 1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid propylamide 1-(3,4-Dichloro-benzyl)-6-methoxy-2-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid dimethylamide 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(7-methyl-[1, 8]naphthyridin-4-yl)-urea 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(5,6,7,8-tetrahydro-quinolin-4-yl)-urea 1-[2-Benzyl-methyl-amino)-pyridinyl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea 1-[2-(Benzyl-methyl-amino)-6-methyl-pyridin-4-yl]-3-{2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-urea 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-[2-(methyl-phenyl-amino)-pyridinyl]-urea 1-{2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-pyrrolidin-1-yl-pyridin-4-yl)-urea 1-{2-[1-4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-3-(2-methylamino-1-yl-pyridin-4-yl)-urea Quinolin-4-yl-carbamic acid 2-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester Quinolin-4-yl-carbamic acid 2-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl ester Quinolin-4-yl-carbamic acid 2-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl ester Quinolin-4-yl-carbamic acid 3-(1-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl ester Quinolin-4-yl-carbamic acid 3-(6,7-dimethoxy-1-phenethyl-3,4-dihydro-1H-isoquinolin-2-yl]-propyl ester Quinolin-4-yl-carbamic acid 3-[1-(3,4-difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl ester Quinolinyl-carbamic acid 3-[1-(3,4-dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl ester Quinolin-4-yl-carbamic acid 3-[1-(4-fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-propyl ester and pharmaceutically acceptable salts thereof.
 18. Pharmaceutical compositions containing a compound of any one of claims 1 to 17 and usual carrier materials and adjuvants for the treatment of disorders which are associated with a dysregulation of urotensin II or urotensin II receptors, especially disorders associated with vascular or myocardial dysfunction, such as hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis.
 19. Pharmaceutical compositions containing a compound of any one of claims 1 to 17 and usual carrier materials and adjuvants for the treatment of disorders such as prevention of restenosis after balloon or stent angioplasty, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addictions, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, epileptic seizures, stress, depression, dementias, neuromuscular disorders, neurodegenerative diseases.
 20. The use of one or more compounds of any one of claims 1 to 17 in combination with other pharmacologically active compounds for the treatment as hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis, restenosis after balloon or stent angioplasty, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addiction, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, seizures, stress, depression.
 21. The use of one or more compounds of any one of claims 1 to 17 in combination with other pharmacologically active compounds such as ACE inhibitors, angiotensin II receptor antagonists, endothelin receptor antagonists, vasopressin antagonists, beta-adrenergic antagonists, alpha-adrenergic antagonists, vasopressin antagonists, TNFalpha antagonists, or peroxisome proliferator activator receptor modulators for the treatment of disorders given in any one of claims 18 to
 20. 22. The entire invention as herein before described. 